Bottom Line:
Fixed rate response was measured before and after each variable period and average force was calculated.We observed no significant change in force at 4 Hz (n=17), and 6 Hz (n=6) between fixed and variable pacing but observed a significant, 10% increase in contractile strength at 8 Hz (from 15.1 to 16.5 mN/mm(2), p<0.05, n=6).Our results show that under certain conditions, by simply introducing variation in the beat-to-beat duration without affecting the number of beats per minute, a positive inotropic effect with corresponding changes in the calcium transients can be generated.

ABSTRACTThere is an intense search for positive inotropic strategies. It is well known that the interbeat duration is a critical determinant of cardiac contractility. Generally, when frequency increases, so does contractile strength. We hypothesize that the beat-to-beat variability at a given heart rate also modulates cardiac contractility. To test this hypothesis, thin, uniform rat cardiac trabeculae were isolated from the right ventricle and stimulated to isometrically contract, alternating between fixed steady state versus variable inter-beat intervals (same total number of beats in each period). Trabeculae were stimulated at 4 Hz with interbeat variation between 20 and 120% (n=17). In a second series of experiments trabeculae were stimulated at 3 different physiologic frequencies with a 40% interbeat variation. Fixed rate response was measured before and after each variable period and average force was calculated. In order to investigate the mechanism underlying the changes in contractility we used iontophoretically loaded bis-fura-2 salt to monitor intracellular calcium transients. We observed no significant change in force at 4 Hz (n=17), and 6 Hz (n=6) between fixed and variable pacing but observed a significant, 10% increase in contractile strength at 8 Hz (from 15.1 to 16.5 mN/mm(2), p<0.05, n=6). Our results show that under certain conditions, by simply introducing variation in the beat-to-beat duration without affecting the number of beats per minute, a positive inotropic effect with corresponding changes in the calcium transients can be generated.

Figure 5: At an average cycle rate of 125 ms (8 Hz), a variation in inter-beat duration of 40% was applied. The correlation between the developed calcium transient and peak active force development (Fdev) is shown in panel A (R2 = 0.57, p=0.03) . Panel B demonstrates the positive correlation between the variations in cycle length and the developed calcium transients (R2 = 0.72, p=0.0006). In panel C, the top and bottom panel show the resulting intracellular calcium transients and twitch contractions respectively. The variation in inter-beat duration is associated with variations in the calcium transients.

Mentions:
When beat-to-beat variability is imposed on cardiac trabeculae the effect of these interval dependent changes on the calcium transients can be seen in Fig. (5). In Fig. (5A), a positive correlation between the developed calcium transient amplitude and force of contraction (Fdev) was observed (P<0.05) under all tested conditions. In Fig. (5B) we demonstrate the positive correlation between a longer cycle length (pre-beat duration) with an increase in the corresponding calcium transient. In addition in Fig. (5C) the variations in interbeat duration and their associated fluctuations in the amplitude of the calcium transients are depicted.

Figure 5: At an average cycle rate of 125 ms (8 Hz), a variation in inter-beat duration of 40% was applied. The correlation between the developed calcium transient and peak active force development (Fdev) is shown in panel A (R2 = 0.57, p=0.03) . Panel B demonstrates the positive correlation between the variations in cycle length and the developed calcium transients (R2 = 0.72, p=0.0006). In panel C, the top and bottom panel show the resulting intracellular calcium transients and twitch contractions respectively. The variation in inter-beat duration is associated with variations in the calcium transients.

Mentions:
When beat-to-beat variability is imposed on cardiac trabeculae the effect of these interval dependent changes on the calcium transients can be seen in Fig. (5). In Fig. (5A), a positive correlation between the developed calcium transient amplitude and force of contraction (Fdev) was observed (P<0.05) under all tested conditions. In Fig. (5B) we demonstrate the positive correlation between a longer cycle length (pre-beat duration) with an increase in the corresponding calcium transient. In addition in Fig. (5C) the variations in interbeat duration and their associated fluctuations in the amplitude of the calcium transients are depicted.

Bottom Line:
Fixed rate response was measured before and after each variable period and average force was calculated.We observed no significant change in force at 4 Hz (n=17), and 6 Hz (n=6) between fixed and variable pacing but observed a significant, 10% increase in contractile strength at 8 Hz (from 15.1 to 16.5 mN/mm(2), p<0.05, n=6).Our results show that under certain conditions, by simply introducing variation in the beat-to-beat duration without affecting the number of beats per minute, a positive inotropic effect with corresponding changes in the calcium transients can be generated.

ABSTRACTThere is an intense search for positive inotropic strategies. It is well known that the interbeat duration is a critical determinant of cardiac contractility. Generally, when frequency increases, so does contractile strength. We hypothesize that the beat-to-beat variability at a given heart rate also modulates cardiac contractility. To test this hypothesis, thin, uniform rat cardiac trabeculae were isolated from the right ventricle and stimulated to isometrically contract, alternating between fixed steady state versus variable inter-beat intervals (same total number of beats in each period). Trabeculae were stimulated at 4 Hz with interbeat variation between 20 and 120% (n=17). In a second series of experiments trabeculae were stimulated at 3 different physiologic frequencies with a 40% interbeat variation. Fixed rate response was measured before and after each variable period and average force was calculated. In order to investigate the mechanism underlying the changes in contractility we used iontophoretically loaded bis-fura-2 salt to monitor intracellular calcium transients. We observed no significant change in force at 4 Hz (n=17), and 6 Hz (n=6) between fixed and variable pacing but observed a significant, 10% increase in contractile strength at 8 Hz (from 15.1 to 16.5 mN/mm(2), p<0.05, n=6). Our results show that under certain conditions, by simply introducing variation in the beat-to-beat duration without affecting the number of beats per minute, a positive inotropic effect with corresponding changes in the calcium transients can be generated.